Cerebral aneurysm is said to be present in 2% to 5% of a general population. In recent years, cases where the presence of cerebral aneurysm is found have rapidly increased along with the spread of a medical checkup of brain or a brain testing. Subarachnoid hemorrhage is a disease mainly caused by rupture of cerebral aneurysm, which has a high mortality, and patients with subarachnoid hemorrhage suffer from severe aftereffects or higher brain dysfunctions in many cases even when the patients survive. In addition, when cerebral aneurysm is found in an unruptured state, a surgical treatment, such as surgical clipping involving craniotomy and coil embolization, is conducted at present as a method for prevention of the rupture of cerebral aneurysm. Such surgical treatment is severely burdensome for patients and a surgical risk is often higher than the risk of the rupture of untreated aneurysm, and therefore the development of noninvasive pharmacotherapy has been desired. Hitherto, there have been several reports on the possibility of pharmacotherapy (Patent documents 1 to 5 and the like), but there has not yet been any established drug therapy. Thus, a drug for the inhibition of formation and/or enlargement of cerebral aneurysm or for the regression of cerebral aneurysm has been desired.
The mechanism of formation of cerebral aneurysm has not yet been sufficiently elucidated. However, for example, it has been reported that high hemodynamic stress conditions are observed at human cerebral aneurysm development sites (Non-Patent document 1), and cerebral aneurysm is induced in a rat by applying high hemodynamic stress (Non-Patent documents 2 and 3). In addition, it has been reported that, in experimentally induced cerebral aneurysm, vascular remodeling occurs at the site to which high hemodynamic stress is applied (Non-Patent document 4). Based on those reports, it has been speculated that cerebral aneurysm is a disease which is induced by hemodynamic stress. Further, it has been thought that the dysfunction of vascular endothelial cells, apoptosis, inflammation, and the like play important roles in the process of formation of cerebral aneurysm. In Non-Patent document 5, for example, it has been reported that endothelial nitric oxide synthase (eNOS) and tumor necrosis factor-α (TNF-α) are involved in the dysfunction of vascular endothelial cells, TNF-α is involved in apoptosis, and the activation of nuclear factor kappa B (NF-κB) by TNF-α, monocyte chemotactic protein-1 (MCP-1), and vascular cell adhesion protein 1 (VCAM-1) is involved in inflammation.
Incidentally, sphingosine 1-phosphate (hereinafter referred to as “SIP”) is one kind of lipid mediator which is produced in the process of the metabolism of sphingolipids and which acts on various cells. A SIP receptor is a G-protein-coupled receptor and five subtypes of the SIP receptor (S1P1 receptor to S1P5 receptor) have been identified. All of these receptors are broadly distributed in cells and tissues throughout the body, but the S1P1 receptor, the S1P3 receptor, and the S1P4 receptor are predominantly expressed in lymphocytes and vascular endothelial cells, the S1P2 receptor is predominantly expressed in vascular smooth muscle cells, and the S1P5 receptor is predominantly expressed in brain and spleen, and amino acid sequences thereof are well conserved among humans and rodents. SIP and its receptors are essential for formation and development of nascent blood vessels and nervous systems, and are involved in immune functions in vivo. Further, it has been found that, also in the cardiovascular system, SIP is involved in the barrier function of endothelial cells, angiogenesis, arteriosclerosis, and vascular and myocardial remodeling (Non-Patent document 6).
A S1P1 receptor agonist is known to induce the downregulation of the S1P1 receptor on lymphocytes and to inhibit the S1P1 receptor-dependent transfer of lymphocytes from secondary lymphoid tissues in immunoreactions involving lymphocytes. Therefore, the S1P1 receptor agonist is expected to exhibit effectiveness in the prevention or treatment of a disease caused by undesired lymphocyte infiltration, for example, transplant rejection of organs, bone marrow, or tissues, an autoimmune disease, such as rheumatoid arthritis, and multiple sclerosis, and an inflammatory disease, such as cerebrospinal meningitis, hepatitis and inflammatory bowel disease, and a large number of compounds each serving as the S1P1 receptor agonist have been reported (Patent documents 6, 7, and 8 and the like). In Patent document 8, there are listed a large number of diseases, as diseases involving EDG-1 (S1P1), for example, varicose vein, such as hemorrhoid, anal fissure and anal fistula, and dissecting aneurysm, but there is no disclosure of cerebral aneurysm.
Meanwhile, there are also various reports on in vivo roles of the signaling via the S1P receptor. With regard to the relationship between the S1P receptor and inflammatory substances regulated via the S1P receptor, it has been reported that S1P increases mRNAs of IL-8 and MCP-1, which are involved in inflammation via the S1P1 receptor and the S1P3 receptor in normal human umbilical vein endothelial cells (HUVECs) (Non-Patent document 7). Meanwhile, it has been reported that S1P inhibits the activation of NF-κB via the S1P1 receptor, and S1P inhibits the expressions of mRNAs of inflammatory substances which are induced by the treatment with lipopolysaccharide (LPS), such as TNFα and MCP-1, in murine macrophages (Non-Patent document 8). In addition, it has been reported that S1P and the S1P1 receptor agonist inhibit LPS-induced TNFα production by murine macrophages, and the inhibitory action of S1P and the S1P1 receptor agonist on the TNFα production is inhibited by a S1P1 receptor antagonist (Non-Patent document 8).
Further, with regard to the roles of the S1P1 receptor expressed in vascular endothelial cells, there is a report suggesting that a signal mediated by the S1P1 receptor enhances adherens junction between cells so that excess buddings of blood vessels are inhibited to stabilize new blood vessels, and besides, the S1P1 receptor plays a role of stabilizing new blood vessels which are activated by responding not only to its ligand S1P, but also to the shear stress of hemodynamic (Non-Patent document 9).
As described above, the mechanism of formation of cerebral aneurysm has not yet been sufficiently elucidated. With regard to a method for the prevention or treatment of enlargement or rupture of cerebral aneurysm, the development of a method which is not performed by a surgical procedure, such as surgical clipping involving craniotomy or coil embolization involving an intravascular surgery, has been desired.